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A. Properties of NO [1,2]navigator

  1. Formerly called EDRF (endothelial derived relaxing factor)
  2. Overview of Biological Activities of NO
    1. Potent relaxer of smooth muscle including blood vessel, esophageal, bronchial
    2. Production of NO in brain inhibits alpha adrenergic tone and sympathetic outflow
    3. Inhibits platelet aggregation
    4. Inhibits smooth muscle proliferation
    5. Inflammatory mediator (particularly in combination with reactive oxygen species, ROS)
    6. In this regard, plays a role in host defense against microbes
    7. Roles in male sexual dysfunction and muscular dystrophy
  3. Synthesis
    1. Derived from L-arginine (Arg) by nitric oxide synthetase (NOS)
    2. Leads to formation of NO and citrulline
  4. Three Type of NOS
    1. Type I NOS (NOS1): neuronal (nNOS) - neurotransmitter
    2. Type II (NOS2): inducible (iNOS) - involved in inflammation
    3. Type III (NOS3): endothelial (eNOS or constitutive cNOS)
  5. Regulation of NO production
    1. Oxidized LDL inhibit NO production
    2. Asymmetric dimethylarginine (ADMA) is endogenous inhibitor of NOS
    3. Superoxide and other toxic oxygen combine with nitric oxide and inactivate it
    4. Superoxide + nitric oxide form peroxynitrite radicals which are toxic to endothelium
    5. ADMA levels are associated with endothelial dysfunction, cardiovascular disease and insulin resistance [9]
    6. Serum levels of ADMA are elevated in women who subsequently develop PIH associated syndromes [13]
    7. Upregulation of iNOS in sepsis syndrome[18] triggers apoptosis of neurons in cardiovascular autonomic (sympathetic) centers and exacerbates hypotension [16]
  6. Utility of Inhaled NO
    1. Selective pulmonary vasodilator, improves ventilation-perfusion matching at low doses
    2. Inhaled NO usually given through mechanical ventilation, also delivered through face-mask
    3. Levels <40 ppm are very safe (essentially no risk of methemoglobinemia)
    4. Treatment of primary and secondary pulmonary hypertension (P-HTN) [3]
    5. Prevention of P-HTN following congenital heart surgery [4]
    6. Premature infants with respiratory distress syndrome [15]
    7. Inhaled NO reduces risk of BPD in premature infants, particularly >1000 gm [21,22]
    8. Inhaled NO reduces risk of any chronic lung disease and improved neurodevelopment in premature infants [22,23]
    9. NO improved oxygenation (but not clinical outcomes) in acute lung injury [17]
    10. NO reduced in sickle cell anemia [24]; supplementation may be beneficial [25]
    11. May have anti-inflammatory (mainly anti-neutrophil) activities
  7. Biochemical Fates of Inhaled Nitric Oxide [1]
    1. NO is poorly reactive with most biomolecules
    2. Can react rapidly with free radicals, certain amino acids, transition metal ions
    3. Small amounts of nitrogen dioxide (NO2) when NO combines with O2 in air space
    4. NO can also react with with reactive oxygen species (ROS such as H2O2)
    5. ROS reaction with NO can lead to formation of peroxynitrite (-NO2) which is toxic
    6. In vascular space, NO is sacenvged by oxyhemoglobin forming methemoglobin and nitrate
    7. Most absorbed NO is converted to nitrate and excreted in urine
  8. Polymorphisms of eNOS
    1. Gene is 21kb encoded on chromosome 7q35-36
    2. Promoter polymorphism T->C at -786 associated with reduced transcription
    3. T->C allele associated with increased coronary spasm and venous thromboembolism
    4. Exon 7 (Glu298->Asp), but not a promoter, polymorphism associated with systemic sclerosis []
  9. Polymorphism of iNOS (NOS2) [11]
    1. NOS2 promoter polymorphism -1173 C/T associated with elevated NO production
    2. NOS2 promoter polymorphism -1173 C/T associated with 8X reduced risk for cerebral malaria and 4X reduced risk of severe malarial anemia
    3. NO appears to protect against severe malaria

B. Nitrates [5,6]navigator

  1. Increase nitric oxide production, primarily affect endothelium
  2. At low doses, vasodilatory effects more prominant on veins than on arterioles
    1. However, low doses do dilate epicardial cardiac arteries
    2. Low doses do not affect coronary resistance vessels
    3. Therefore, have reduced risk of inducing coronary "steal" syndromes
    4. These effects may be reversed in Type II diabetic patients [7]
  3. Anticlotting Activities
    1. Reduce platelet aggregation
    2. Reduce blood viscosity
    3. Increase blood filterability
  4. Clearly improve anginal symptoms but little data support major changes in outcomes in patients with acute coronary syndromes
  5. Good Activity in Congestive Heart Failure
    1. High dose hydralazine+isosorbide beneficial in CHF without maximal angiotensin blockade [19]
    2. Isosorbide dinitrate (40mg tid) and hydralazine (75mg tid) is clearly beneficial in black CHF patients with full ACE-I or ARB blockade [20]
  6. Relax lower esophageal sphincter at typical doses

C. Nitroglycerinnavigator

  1. Direct acting vasodilator, venous > arterial
  2. Dilates large epicardial arteries with little effect on intramyocardial vessels
  3. Treatment of angina in patients with coronary artery disease
  4. Tolerance to IV (Nitro-Bid®, Nitrostat®, Tridil®) nitroglycerin develops within 24 hours
  5. Oral Nitrates [8]
    1. Isosorbide Dinitrate (Isordil®): usual dose 20-40 mg bid-tid
    2. Isosorbide Mononitrate (Ismo®): usual dose 10-40mg po qd
  6. Often used transdermally (Nitro-Dur®, Transderm-Nitro®) as patches
  7. Paste preparation is available, dosed in inches q4-6 hours
  8. Sublingual (Nitrostat®, Nitroglycerin®)

D. Sodium Nitroprusside (Nipride®, Nitropress®) navigator

  1. Very potent arterial and moderately potent venous dilator; rapid acting iv only
  2. Cardiac output unchanged and tachyphylaxis uncommon
  3. Used to treat hypertensive emergencies
  4. May also be used for afterload reduction
    1. Severe pulmonary edema (particularly with hypertension)
    2. Severe aortic stenosis and reduced left ventricular ejection fraction [12]
  5. Very short half life; completely depleted within 3 minutes. Used at 0.5-10µg/kg/min
  6. Main concern in renal insufficiency is buildup of cyanides (thiocyanate)

E. Summary of Properties of Nitratesnavigator

Nitrate CompoundVenousArterialComments
Nitroglycerin IV4+2+· must have bp monitoring
Nitroprusside IV3+4+· must have bp monitoring
Isosorbide Dinitrate4+1+· begin 10mg bid-tid (usually tid)
Isosorbide Mononitrate4+1+· begin 5-10mg po qd-bid
Nitroglycerin Patch4+1+· begin with 2.5-7.5mg tid,hold 12MN-8AM

F. NOS Inhibitorsnavigator
  1. L-NAME (N-nitro-L-arginine methyl ester)
    1. NO synthetase inhibitor
    2. Elevated NO levels in cirrhosis contribute to A-a gradient
  2. L-NAME in hepatopulmonary syndrome [14]
    1. L-NAME studied in a patient with viral induced cirrhosis and hepatopulmonary syndrome
    2. Aerosolized L-NAME enhanced oxygenation by >30% and improved walking distance ~40%

G. Other Drugs Affecting Nitric Oxidenavigator

  1. Statins increase eNOS activity
  2. Estrogen replacement therapy increases both eNOS and nNOS
  3. ACE inhibitors increase bradykinin, which activates eNOS

References navigator

  1. Griffiths MJ and Evans TW. 2005. NEJM. 353(25):2683 abstract
  2. Murad F. 2006. NEJM. 355(19):2003 abstract
  3. Higenbottam T, Siddons T, Demoncheaux E. 2000. Lancet. 356(9228):446 abstract
  4. Miller OI, Tang SF, Keech A, et al. 2000. Lancet. 356(9240):1464 abstract
  5. Parker JD and Parker JO. 1998. NEJM. 338(8):1998 abstract
  6. Sixth Report by JNC on Hypertension (JNC-VI). 1997. Arch Intern Med. 157(21):2413 abstract
  7. Giugliano D, Marfella R, Verrazzo G, et al. 1995. Ann Intern Med. 123(5):338 abstract
  8. Isosorbide Mononitrate. 1994. Med Let. 36(915):13 abstract
  9. Stuhlinger MC, Abbasi F, Chu JW, et al. 2002. JAMA. 287(11):1420 abstract
  10. Fatini C, Gensini F, Sticchi E, et al. 2002. Am J Med. 112(7):540 abstract
  11. Hobbs MR, Udhayakumar V, Levesque MC, et al. 2002. Lancet. 360(9344):1468 abstract
  12. Khot UN, Novaro GM, Popovic ZB, et al. 2003. NEJM. 348(18):1756 abstract
  13. Savvidou MD, Hingorani A, Tsikas D, et al. 2003. Lancet. 361(9368):1511 abstract
  14. Brussino L, Bucca C, Morello M, et al. 2003. Lancet. 362(9377):43 abstract
  15. Schreiber MD, Gin-Mestan K, Marks JD, et al. 2003. NEJM. 349(22):2099 abstract
  16. Sharshar T, Gray F, de la Grandmaison GL, et al. 2003. Lancet. 362(9398):1799 abstract
  17. Taylor RW, Zimmerman JL, Dellinger RP, et al. 2004. JAMA. 291(13):1603 abstract
  18. Schrier RW and Wang W. 2004. NEJM. 351(2):159 abstract
  19. Cohn JN, Johnson G, Ziesche S, et al. 1991. NEJM. 325(5):303 abstract
  20. Taylor AL, Ziesche S, Yancy C, et al. 2004. NEJM. 351(20):2049 abstract
  21. Van Meurs KP, Wright LL, Ehrenkranz RA, et al. 2005. NEJM. 353(1):13 abstract
  22. Schrieber MD, Gin-Mestan K, Marks JD, et al. 2003. NEJM. 349:2099 abstract
  23. Mestan KKL, Marks JD, Hecox K, et al. 2005. NEJM. 353(1):23 abstract
  24. Morris CR, Kato GJ, Poljakovic M, et al. 2005. JAMA. 294(1):81 abstract
  25. Weiner DL, Hibberd PL, Betit P, et al. 2003. JAMA. 289(9):1136 abstract